DESCRIPTION (Applicant's Description) Werner syndrome (WS) is a disease characterized by genetic instability and an unusually high incidence of specific cancers. The objective of the applicants is to understand the mechanistic bases of genetic instability and cancer in WS. The WS gene may have broader public health implications, since heterozygotic carriers are frequent. Mutations in the gene, inherited in carriers and arising spontaneously in non-carriers, could be causally related to the occurrence of specific cancers in the general population. Moreover, because the WS gene product is a DNA helicase, the proposed program project will provide fundamental information concerning the roles of helicases in maintenance of genomic integrity and avoidance of cancer. The applicants are uniquely positioned, in terms of knowledge, resources, and technology, to exploit new opportunities stemming from the recent cloning of the WS gene and expression of the catalytically active WS helicase. The proposed program encompasses five interrelated projects that use complementary experimental approaches to investigate genetic instability in WS at different levels of biological organization, and two supporting core components. Major aims of the five projects, respectively, are to: (1) Characterize wild- type and mutant WS helicases; (2) analyze the role of the WS gene product in DNA replication in yeast; (3) study genetic instability in cultured cells due to mutation in the WS helicase; (4) determine the effect of mutations in the WS gene on the cell cycle and on the cellular response to DNA damage; (5) establish mice that are homozygotic or heterozygotic at the WS locus and analyze genomic instability and the incidence of tumors in response to carcinogens.